Upon detection of active oxygen species, etc., generated in the course of energy metabolism, host defense systems such as antioxidative enzyme groups, detoxification metabolism enzyme groups or the like are initiated. The Keap1/Nrf2/ARE signaling pathway controls the initiation of this host defense system.
It is known that the activation of the Keap1/Nrf2/ARE signaling pathway induces its target gene of NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase-1 (HO-1), γ-glutamate cysteine ligase catalytic subunit (GCLC), or the like (Non-patent Literature 1). NQO1 is a phase 2 enzyme of xenobiotic metabolism and is important for detoxification. HO-1 and GCLC are known as typical antioxidative enzymes. When these enzymes are increased in amount or activated, the cells become resistant to poison, oxidative stress, inflammation, etc. Compounds that activate this signaling pathway are therefore considered to serve as therapeutic drugs for various diseases (Non-patent Literatures 2 to 5). Specific examples of the targeted diseases are as given below.
Nrf2-deficient mice have been reported to exhibit vulnerability in the retinal ischemia/reperfusion system (Non-patent Literature 6). This suggests the applicability to the compounds to eye diseases such as allergic conjunctival disease, viral conjunctivitis, pterygium, corneal infection, corneal endothelial disorder, uveitis, Behcet's disease, diabetic retinopathy, retinal detachment, retinal vein occlusion, central serous chorioretinopathy, age-related macular degeneration, diabetic macular edema, macular disease, retinitis pigmentosa, glaucoma, and cataract (Non-patent Literatures 7 and 8).
Nrf2-deficient mice have been reported to exhibit vulnerability to cisplatin-induced nephrotoxicity (Non-patent Literature 9). This suggests the applicability of the compounds to renal diseases such as acute nephritis, chronic nephritis, acute renal failure, chronic renal failure, nephrotic syndrome, IgA nephropathy, diabetic nephropathy, gouty kidney, nephrosclerosis, hydronephrosis, tubulointerstitial nephritis, and urinary tract infection (Non-patent Literature 10).
Nrf2-deficient mice have been reported to exhibit vulnerability to cigarette smoke exposure (Non Patent Literature 11). This suggests the applicability of the compounds to respiratory diseases such as bronchitis, pneumonia, pleuritis, chronic obstructive pulmonary disease, diffuse panbronchiolitis, pulmonary emphysema, and asthma (Non-patent Literatures 12 and 13).
Nrf2-deficient mice have been reported to be likely to develop non-alcoholic steatohepatitis when fed with methionine/choline-deficient diet (Non-patent Literature 14). This suggests the applicability of the compounds to hepatic diseases such as alcoholic fatty liver, non-alcoholic steatohepatitis, hepatic fibrosis, and liver cirrhosis (Non-patent Literatures 2 and 15).
Also, Nrf2 activators have been reported to exhibit hypoglycemic action in mice (Non-patent Literature 16). This suggests the applicability of the compounds to diabetes mellitus and its complications (diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy) or the like.
As substances that activate the Keap1/Nrf2/ARE signaling pathway, sulforaphane contained in broccoli sprouts, curcumin contained in turmeric for curry, or the like have been reported to activate Nrf2 and promote the detoxification of carcinogens (Non-patent Literature 17). Also, a 5-membered ring triterpenoid comprising methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-acid (Non-patent Literature 18 and Patent Literatures 1 to 9) discovered by Honda et al. has been reported to activate the Keap1/Nrf2/ARE signaling pathway. These compounds have been reported to bring about the production of several anti-inflammatory proteins and antioxidative proteins (e.g., NQO1, HO-1, and GCLC) (Patent Literature 9).